Crosstalk between the M1 muscarinic acetylcholine receptor and the endocannabinoid system: A relevance for Alzheimer's disease?

Alzheimer's disease (AD) is a neurodegenerative disorder which accounts for 60-70% of the 50 million worldwide cases of dementia and is characterised by cognitive impairments, many of which have long been associated with dysfunction of the cholinergic system. Although the M muscarinic acetylcholine receptor (mAChR) is considered a promising drug target for AD, ligands targeting this receptor have so far been unsuccessful in clinical trials. As modulatory receptors to cholinergic transmission, the endocannabinoid system may be a promising drug target to allow fine tuning of the cholinergic system. Furthermore, disease-related changes have been found in the endocannabinoid system during AD progression and indeed targeting the endocannabinoid system at specific disease stages alleviates cognitive symptoms in numerous mouse models of AD. Here we review the role of the endocannabinoid system in AD, and its crosstalk with mAChRs as a potential drug target for cholinergic dysfunction. [Abstract copyright: Copyright © 2019. Published by Elsevier Inc.

Predicted Colors and Flux Densities of Protostars in the Herschel PACS and SPIRE Filters

Upcoming surveys with the Herschel Space Observatory will yield far-IR photometry of large samples of young stellar objects, which will require careful interpretation. We investigate the color and luminosity diagnostics based on Herschel broad-band filters to identify and discern the properties of low-mass protostars. We compute a grid of 2,016 protostars in various physical congurations, present the expected flux densities and flux density ratios for this grid of protostars, and compare Herschel observations of three protostars to the model results. These provide useful constraints on the range of colors and fluxes of protostar in the Herschel filters. We find that Herschel data alone is likely a useful diagnostic of the envelope properties of young starsComment: Part of HOPS KP papers to the Herschel special A&A issu

An evolutionary perspective on the kinome of malaria parasites

Malaria parasites belong to an ancient lineage that diverged very early from the main branch of eukaryotes. The approximately 90-member plasmodial kinome includes a majority of eukaryotic protein kinases that clearly cluster within the AGC, CMGC, TKL, CaMK and CK1 groups found in yeast, plants and mammals, testifying to the ancient ancestry of these families. However, several hundred millions years of independent evolution, and the specific pressures brought about by first a photosynthetic and then a parasitic lifestyle, led to the emergence of unique features in the plasmodial kinome. These include taxon-restricted kinase families, and unique peculiarities of individual enzymes even when they have homologues in other eukaryotes. Here, we merge essential aspects of all three malaria-related communications that were presented at the Evolution of Protein Phosphorylation meeting, and propose an integrated discussion of the specific features of the parasite's kinome and phosphoproteome

The use of chemogenetic approaches to study the physiological roles of muscarinic acetylcholine receptors in the central nervous system

Chemical genetic has played an important role in linking specific G protein-coupled receptor (GPCR) signalling to cellular processes involved in central nervous system (CNS) functions. Key to this approach has been the modification of receptor properties such that receptors no longer respond to endogenous ligands but rather can be activated selectively by synthetic ligands. Such modified receptors have been called Receptors Activated Solely by Synthetic Ligands (RASSLs) or Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Unlike knock-out animal models which allow detection of phenotypic changes caused by loss of receptor functions, RASSL and DREADD receptors offer the possibility of rescuing "knock-out" phenotypic deficits by administration of the synthetic ligands. Here we describe the use of these modified receptors in defining the physiological role of GPCRs and validation of receptors as drug targets

On the nature of the deeply embedded protostar OMC-2 FIR 4

We use mid-infrared to submillimeter data from the Spitzer, Herschel, and APEX telescopes to study the bright sub-mm source OMC-2 FIR 4. We find a point source at 8, 24, and 70 $\mu$m, and a compact, but extended source at 160, 350, and 870 $\mu$m. The peak of the emission from 8 to 70 $\mu$m, attributed to the protostar associated with FIR 4, is displaced relative to the peak of the extended emission; the latter represents the large molecular core the protostar is embedded within. We determine that the protostar has a bolometric luminosity of 37 Lsun, although including more extended emission surrounding the point source raises this value to 86 Lsun. Radiative transfer models of the protostellar system fit the observed SED well and yield a total luminosity of most likely less than 100 Lsun. Our models suggest that the bolometric luminosity of the protostar could be just 12-14 Lsun, while the luminosity of the colder (~ 20 K) extended core could be around 100 Lsun, with a mass of about 27 Msun. Our derived luminosities for the protostar OMC-2 FIR 4 are in direct contradiction with previous claims of a total luminosity of 1000 Lsun (Crimier et al 2009). Furthermore, we find evidence from far-infrared molecular spectra (Kama et al. 2013, Manoj et al. 2013) and 3.6 cm emission (Reipurth et al 1999) that FIR 4 drives an outflow. The final stellar mass the protostar will ultimately achieve is uncertain due to its association with the large reservoir of mass found in the cold core.Comment: Accpeted by ApJ, 17 pages, 11 figure

MISALIGNED DISKS IN THE BINARY PROTOSTAR IRS 43

Recent high angular resolution ($\sim$0.2") ALMA observations of the 1.1 mm continuum and of HCO+ J=3-2 and HCN J=3-2 gas towards the binary protostar IRS 43 reveal multiple Keplerian disks which are significantly misaligned ($\gt$ 60$^\circ$), both in inclination and position angle and also with respect to the binary orbital plane. Each stellar component has an associated circumstellar disk while the binary is surrounded by a circumbinary disk. Together with archival VLA measurements of the stellar positions over 25 years, and assuming a circular orbit, we use our continuum measurements to determine the binary separation, a = 74 $\pm$ 4 AU, and its inclination, i $\lt$ 30$^\circ$. The misalignment in this system suggests that turbulence has likely played a major role in the formation of IRS 43.Comment: 7 pages, 4 figure

Distinct phosphorylation clusters determines the signalling outcome of the free fatty acid receptor FFA4/GPR120

It is established that long-chain free fatty acids including ω-3 fatty acids mediate an array of biological responses through members of the free fatty acid receptor family, which includes FFA4. However, the signalling mechanisms and modes of regulation of this receptor class remain unclear. Here we employ mass spectrometry to determine that phosphorylation of mouse (m)FFAR4 occurs at five serine and threonine residues clustered in two separable regions of the C terminal tail, designated cluster 1 (Thr347, Thr349 and Ser350) and cluster 2 (Ser357 and Ser361). Mutation of these phospho-acceptor sites to alanine completely prevented phosphorylation of mFFA4 but did not limit receptor coupling to ERK1/2 activation. Rather an inhibitor of Gq/11 proteins completely prevented receptor signalling to ERK1/2. In contrast, the recruitment of arrestin 3, receptor internalization and activation of Akt were regulated by mFFA4 phosphorylation. The analysis of mFFA4 phosphorylation-dependent signalling was extended further by selective mutations of the phospho-acceptor sites. Mutations within cluster 2 did not affect agonist activation of Akt but instead significantly compromised receptor internalization and arrestin 3 recruitment. Distinctly, mutation of the phospho-acceptor sites within cluster 1 had no effect on receptor internalization and a less extensive effect on arrestin 3 recruitment, but significantly uncoupled the receptor from Akt activation. These unique observations define differential effects on signalling mediated by phosphorylation at distinct locations. This hallmark feature supports the possibility that the signalling outcome of mFFA4 activation can be determined by the pattern of phosphorylation (phosphorylation barcode) at the C-terminus of the receptor

Financial Transaction Tax: Small is Beautiful

The case for taxing financial transactions merely to raise more revenues from the financial sector is not particularly strong. Better alternatives to tax the financial sector are likely to be available. However, a tax on financial transactions could be justified in order to limit socially undesirable transactions when more direct means of doing so are unavailable for political or practical reasons. Some financial transactions are indeed likely to do more harm than good, especially when they contribute to the systemic risk of the financial system. However, such a financial transaction tax should be very small, much smaller than the negative externalities in question, because it is a blunt instrument that also drives out socially useful transactions. There is a case for taxing over-the-counter derivative transactions at a somewhat higher rate than exchange-based derivative transactions. More targeted remedies to drive out socially undesirable transactions should be sought in parallel, which would allow, after their implementation, to reduce or even phase out financialtransaction taxes